A Dynamic Bronchial Airway Gene Expression Signature of COPD and Lung Function Impairment.

Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts, United States.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 11.99). 03/2013; 187(9). DOI: 10.1164/rccm.201208-1449OC
Source: PubMed

ABSTRACT RATIONALE: Molecular phenotyping of COPD has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function. OBJECTIVES: We sought to determine whether COPD-associated processes are reflected in gene-expression profiles of bronchial airway epithelial cells obtained via bronchoscopy. METHODS: Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays. MEASUREMENTS AND MAIN RESULTS: We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified ATF4 as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline following therapy with the inhaled corticosteroid fluticasone in independent cohorts. CONCLUSIONS: Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may therefore ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD.

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